Intermediate for producing semi-synthetic penicillins and cephalosporins

ABSTRACT

Novel 6-APA, 7-ACA, and 7-ADCA derivatives are described which comprise phosphorylated derivatives of 6-APA, 7-ACA, or 7-ADCA and the corresponding acylated derivatives thereof. The novel compounds are prepared by the reaction of 6-APA, 7-ACA, 7-ADCA or a salt thereof with a phosphorus halide in the presence of an acid acceptor and subsequently acylating the thus formed phosphorylated compound, to form a phosphorylated acylated derivative which upon hydrolysis with water splits off the protective group(s) to provide the corresponding semi-synthetic penicillin or cephalosporin having useful antibacterial activity.

This application is a division of application Ser. No. 197,142 filedNov. 9, 1971, now U.S. Pat. No. 3,859,298.

This invention relates to novel phosphorylated 6-APA, 7-ACA, and 7-ADCAderivatives, acylated derivatives thereof and the process for theirproduction.

One aspect of the present invention relates to the production ofsemi-synthetic penicillins and cephalosporins in high yields fromcompounds such as 6-amino penicillanic and, 7-amino cephalosporanicacid, and 7-amino-3-desacetoxy cephalosporanic acid.

Another aspect of the present invention relates to the acylation ofnovel phosphorylated 6-amino penicillanic acids, 7-amino cephalosporanicacids, and 7-amino-3-desacetoxy cephalosporanic acids in the absence ofan acid acceptor.

Yet another aspect of the present invention relates to novel acylatedand phosphorylated derivatives of 6-amino penicillanic acid, 7-aminocephalosporanic acid, 7-amino-3-desacetoxy cephalosporanic acid andrelated compounds.

These and other aspects of the present invention will become apparentfrom the following description.

In its broadest aspects the present invention covers compounds havingthe following structure: ##SPC1##

Wherein:

R is a member selected from the class consisting of hydrogen and anorganic acyl radical; R¹ is selected from the class consisting ofhydrogen and a radical of the formula ##EQU1## with the proviso that Rand R¹ are not both hydrogen; R² is a member selected from the classconsisting of R¹, alkali metal (e.g. Na, K) and a tertiary amine;

R⁴ is a member selected from the class consisting of hydrogen,(lower)alkanoyloxy containing 2 to 8 carbon atoms, and a quaternaryammonium radical. R⁵ and R⁶ are each selected from the class consistingof (lower) alkyl, aryl, halo(lower)alkyl, aryl(lower)alkyl; and R⁵ andR⁶ may be joined together to form with phosphorus, the ring ##SPC2##

Wherein X is selected from the class consisting of oxygen, CH₂ andsulfur; m is an interger from 1 to 6; R⁷ is hydrogen or (lower)alkyl.

The preferred novel compounds of the present invention are those havingthe following formulae: ##SPC3##

Wherein:

R is selected from the class consisting of hydrogen and organic acyl;

R¹ is selected from the class consisting of hydrogen and ##SPC4##

With the proviso that R and R¹ are not both hydrogen; R⁴ is selectedfrom the class consisting of hydrogen and acetoxy.

The term "(lower)alkyl" as employed herein alone or in conjunction withother designated groups is intended to encompass straight chain orbranch chain alkyl groups consisting of from one through six carbonatoms (e.g. methyl, ethyl, propyl, butyl, isobutyl, hexyl,2-ethylpropyl, etc.)

The term "halogen" as used herein is intended to encompass chlorine,bromine, iodine and fluorine. The term "aryl" encompasses monocyclic andbicyclic rings having six to ten ring carbon atoms such as phenyl,naphthyl, etc. The term "aryl(lower) alkyl" is illustrated by benzyl,phenethyl, etc.

The term "(lower)alkanoyloxy" is illustrated by acetoxy, propionoyloxyand butanolyloxy. The term "quaternary ammonium" is illustrated bypyridinium, quinolinium, picolinum, etc. The term "tertiary amine" isillustrated by any of the well-known radicals such as triethylamine,tribenzylamine, N-ethylpiperidine which are described in the penicillinand cephalosporin art as capable of forming an amine salt with thecarboxyl group.

The acyl group defined by R is derived from an organic carboxylic acidor a suitable functional reactive derivative thereof.

When R is acyl, the preferred acyl radicals are selected from groupshaving the following formulae: ##SPC5##

wherein:

R³ is selected from the class consisting of hydrogen, (lower)alkyl andphenyl; R⁸ and R⁹ are selected from the group consisting of hydrogen and(lower)alkoxy;

R¹⁰ is selected from the class consisting of hydrogen, (lower)alkyl andphenyl;

R¹¹ and R¹² are selected from the class consisting of hydrogen andhalogen;

R¹³ and R¹⁴ are selected from the class consisting of hydrogen, halogen,(lower)alkyl, (lower)alkoxy, phenyl and phenoxy;

a is an interger from 0 to 1; b is an interger from 0 through 5;

c is an interger from 0 through 2; d is an interger from 1 through 3,with the proviso that when a is 0, d is greater than 1, and when a is 1,d is less than 3.

Semi-synthetic penicillins and cephalosporins may be prepared accordingto the following flow diagrams, using 6-APA and 7-ACA respectively, asillustrative starting materials. ##SPC6## ##SPC7##

In the foregoing process the starting material (e.g. 6-APA, 7-ACA or7-ADCA) which may be obtained by any number of procedures described inthe art (e.g. See U.S. Pat. Nos. 3,499,909 and 2,941,995) is reactedwith a phosphorus halide of formula II in the presence of inert organicsolvent and an acid acceptor to form a compound of formula III or VIIrespectively. This reaction is preferably carried out at a temperatureabove -10° C. and not higher than about -25° C. The molar ratio of anacid binding agent to a starting material such as 6-APA is about 0.75:2and the molar ratio of acid binding agent to a compound of formula II is1:1.

Suitable acid binding agents are tertiary amines such as triethyl amine,dimethylaniline, quinoline, pyridine, lutidine, alkali metal carbonates;alkaline earth carbonates or other acid binding agents known in the art.The preferred acid binding agent is a strong tertiary amine. As usedherein "strong amines" are those characterized by having dissociationconstants in the range of from 10⁻ ³ to 10⁻ ⁶ or having comparablebasicity, as distinguished from "weak amines" which are characterized byhaving dissociation constants in the range of from 10⁻ ⁸ to 10⁻ ¹¹.

A wide range of anhydrous non-hydroxylic organic solvents are useful inthe reaction of 6-APA or 7-ACA with a phosphorylating agent includinghydrocarbons such as benzene and toluene; chlorinated solvents such asmethylene chloride, chloroform and chlorobenzene; ethers such as diethylether, dioxane, tetrahydrofuran; and other conventional solvents such asmethylisobutylketone, dimethylformamide, ethyl acetate, acetonitrile,etc.

The reaction between 6-APA, 7-ACA, or 7-ADCA and a phosphorus halide iscarried out preferably at a temperature at which the reaction proceedsto completion in a reasonably short time period, i.e. between -10° C.and +10° C.

A compound of formula III and VII prepared according to this inventioncan be isolated by removing the hydrohalide base by filtration anddistillation of the solvent, or if the intermediate is to be convertedat once to a penicillin or cephalosporin, the reaction mixture can beacylated directly without filtration or concentration.

The product or products obtained from the reaction of a compound offormula I or VI with a phosphorylating agent is dependent on the molarratio of the reactants as to whether an anhydride of the pencillanicacid is formed. Thus, if the molar ratio of a compound of formula II toformula I is greater than 1:1, the predominant material obtained is acompound of formula III, particularly as the molar ratio increases toabout 2:1 and higher. On the other hand where the molar ratio is 1:1 orless (e.g. 0.5:1), the predominant compound is ##SPC8##

with the amount of a compound of formula III becoming smaller as themolar ratio of a compound of formula II is decreased in relation to theamount of 6-APA.

The preferred molar ratio of phosphorylating agent to the startingmaterial such as a compound of formula I or VI is greater than 1:1,preferably at least 2:1.

The fact that mixtures of phosphorylated compounds can be produced undercertain reaction conditions does not interfere with the process ofacylation and subsequent formation of the desired semi-syntheticpenicillin or cephalosporin.

Novel phosphorylated acylated compounds within the scope of formula Aand B may be prepared by the acylation of a compound of formula III orVII in accordance with the reaction sequence shown above in diagrams Aand B, respectively.

Suitable acylating agents include carboxylic acid halides, carboxylicacid anhydrides, mixed anhydrides with other carboxylic or inorganicacids; esters such as thiol esters and phenol esters; lactones; andcarboxylic acids with carbodiimides or N,N¹ -carboxyldiimidazoles.

Illustrative of some specific preferred acylating agents arephenoxyacetyl chloride, 2,6-dimethoxybenzoyl chloride, benzene sulfonylchloride, 2-phenoxypropionyl chloride, 2-phenoxy-butyl chloride,D(-)phenylglycyl chloride HCl, 1-aminocyclopentane-carboxylic acidchloride HCl, 1-aminocyclohexanecarboxylic acid chloride HCl,2-amino-2-carboxyindane acid chloride HCl, 2-ethoxy naphthoyl bromideand 3-(2,6-dichlorophenyl)-5-methyl-isoxazole carbonyl chloride, etc.

In carrying out the acylation step, it has been suprisingly found thatan acid acceptor need not be present during the reaction. Heretoforesuch a reagent was deemed essential for successfully carrying out theacylation procedure as illustrated by U.S. Pat. Nos. 3,595,855;3,249,622. In addition, where a strong amine is used in reacting acompound of formula I with a compound of formula II, it is desirable toavoid the presence of any excess strong amine because the strong aminehas a deleterious effect on the yield of semi-synthetic penicillinproduced. The acylation process is carried out in the presence ofanhydrous inert snhydrous organic solvent. Suitable solvents may be thesame as earlier exemplified for the reaction producing thephosphorylated derivatives of 6-APA, 7-ACA, 7-ADCA, etc.

The acylated penicillins and cephalosporins of formulae IV and IX arereadily hydrolyzed by treating with water, to split off the protectivegroup from the amino group and the carboxyl group to form asemi-synthetic penicillin or cephalosporin embranced by formulae V andX, respectively.

The acylation of a compound of formula III or VII first results in theformation of an intermediate of formula IV(a) or VIII, respectively.These intermediates repidly convert to a compound of formula IV and IX,respectively as a result of expulsion of ##EQU2## from the nitrogenatom. This expulsion is due to the presence of an anion (e.g. Cl⁻) uponformation of the intermediate of formula IV(a) or VIII, respectively,which attacks the phosphorus atom linked to the nitrogen. It is possiblethat the presence of a weak base during the acylation would bind theanion and thereby avoid the expulsion of ##EQU3## In the latter casehydrolysis of a compound of formula IV(a) or VIII, respectively, wouldresult in direct formation of a compound of formula V or X, rather thanintermediate IV or IX.

The hydrolysis is carried out at a pH between 0.5 and 2 at a temperaturebelow about 15°, preferably between 0° and 5° C. The hydrolysis iscarried out by treatment with water.

Where the acylating agent used is in the form of an acid addition salt,the penicillin or cephalosporin of formula V or X is recovered uponhydrolysis as an acid addition salt (e.g. chloride) which may then beconverted to the free base by methods well known in the art. In theevent the ultimate penicillin to be obtained is α-aminobenzyl penicillin(ampicillin), it has been found advantageous to change the chloride toan aryl sulfonic acid salt of the aminopenicillin either by adding anappropriate sulfonic acid to the reaction mixture comprising theselected organic solvent and water, or to the aqueous extracts separatedas described immediately above. In this connection, a 25 percent excessof the sulfonic acid has been used to advantage in preparing thecorresponding salt of ampicillin.

The aryl sulfonic salt of the α-aminobenzyl penicillin may then beconverted to the penicillin per se by reaction with a base such astriethylamine or diethylamine in approximately 85 percent isopropanol.In the case of ampicillin specifically, the sulfonic acid salt, wet withwater and ethyl acetate, may be added to isopropanol containing a molarequivalent of triethylamine at 75°-80°C., whereby the anhydrous form ofampicillin described and claimed in U.S. Pat. No. 3,144,445 is formedand collected by filtration from the hot mixture.

Alternatively, the corresponding penicillin may be obtained, but inhydrated form, by raising the pH of the aqueous reaction mixturecontaining the hydrochloride salt of said penicillin to the iso-electricpoint.

The starting materials defined by formula II may be prepared byprocedures described in the literature. For example, the preparation of2-chloro-1,3,2-dioxaphospholane is described by Lucas et al., J. Am.Chem. Soc. 72, 5491-5497 (1950). Other compounds within the scope offormula II may be prepared by the procedures described by Brown et al.,J. Chem. Soc. 878-881 (1970).

The following examples are given by way of illustration and are not tobe construed as limitations of this invention.

EXAMPLE 1 D(-)α-aminobenzylpenicillin

6-Aminopenicillanic acid (10.81 g, 0.05 mole) is stirred for 1/2 hr. in100 ml. of dichloromethane at 0-5° C. containing 13.85 ml. oftriethylamine. At 0°-5° C., a solution of 12.65 g. (0.1 mole) of2-chloro-1,3,2-dioxaphospholane in 50 ml. of dichloromethane is addedover 1 hr., and the mixture is stirred an additional 1/2 hr. at 0°-5° C.The resulting product is 6-(1,3,2-dioxaphospholan-2-yl amino)penicillanic acid, 1,3,2-dioxaphospholan-2-yl ester. D-(-)phenylglycylchloride hydrochloride (10.63 g., 0.05 mole) is added to the stirredmixture over 2 min., and stirring is continued for 1/2 hr. at 0°-5° C.under nitrogen. The cooling bath is removed and the temperature isallowed to go to 17° C. and held at this temperature for a totalacylation time of 3 hr. The resulting acylated product is 6-(2-amino-2-phenylacetamido)penicillanic acid, 1,3,2-dioxaphosphalan-2-yl ester.The mixture is poured into 300 ml. of water at 0°-5° C. and stirred for15 min., with the pH going to 0.7. Celite is added, the mixture isfiltered, and the filtrate is separated and the water layer (340 ml.) isbioassayed vs. S. Lutea. The addition of 5 ml. of this solution to 245ml. of 1 percent pH 6 buffer gives an assay value of 700 γ/ml. ofampicillin.

The β-naphthalene sulfonic acid salt is prepared from the 340 ml. ofsolution by adding ethyl acetate (40 ml.) and cooling to 0°-10° C.followed by addition of 29.4 g. of a 37,68 percent solution ofβ-naphthalene sulfonic acid over 10 min. and holding the pH at 1.5 to1.7 with the addition of 5N sodium hydroxide. This mixture is stirredovernight at 5°(filtered, stirred in 60 ml. of ethyl acetate for 5 min.,filtered and sucked dry, giving 27.3 g. the β -naphthalene sulfonic acidsalt of D(-)α-aminobenzylpenicillin. It was bioassayed vs. S. Luteaindicating the presence of 560 γ/mg. of ampicillin.

EXAMPLE 2 1-aminocyclohexane penicillin

6-Aminopenicillanic acid (43.25 g., 0.7 mole) is stirred indichloromethane (400 ml.) containing triethylamine (55.6 ml., 0.4 mole)at room temperature until solution is complete. The temperature islowered to 0°-5° C., and 50.6 g. (0.4 mole) 2-chloro-1,32-dioxophospholane in 200 ml. of dichloromethane is added over 1 hr.,and stirring is continued at 0°-5° C. for 1/2 hr.1-aminocyclohexanecarboxylic acid chloride hydrochloride (40 g., 0.2mole) is added, and the mixture is stirred while the internaltemperature is allowed to slowly go to 10° C. over 1/2 hr., and thereaction is continued for an additional 2 1/2 hr. at 10° C. The mixtureis poured into 200 ml. of cold (0°-5° C.) water and the mixture isstirred in an ice bath for 15 min. Isopropanol (160 ml.) and celite (15g.) are added, the mixture is filtered by suction, and the cake iswashed with 40 ml. of isopropanol. The two-phase filtrate is poured intoa 2 liter round bottom 3-neck flask, and while stirring at 15°-20° C.,the pH is raised to 5.4-5.5 with 5N NaOH, giving white crystals ofdihydrate of the above titled compound.

EXAMPLE 3 D(-)-α-aminobenzylpenicillin

6-aminopenicillanic acid (43.25 g., 0.2 mole) is stirred indichloromethane (400 ml.) containing triethylamine (55.6 ml., 0.4 mole)at room temperature until solution is complete. The temperature islowered to 0°-5° C., and 50.6 g. (0.4 mole)2-chloro-1,3,2-dioxophospholane in 200 ml. of dichloromethane is addedover 1 hr., and continue to stir at 0°-5° C. for 1/2 hr.D(-)Phenylglycyl chloride hydrochloride (43.6 g., 0.2 mole) is addedover about 1 min., and the mixture is stirred at 0°-5° C. for 3/4 hr.The ice bath is lowered so that only the lower 1-2 cm. of the flask isin the ice water, and the internal temperature is allowed to slowly(about 25 min.) go to 10° C., and then held at this point for a totaltemperature raising time and reaction time of 2 hr. The mixture ispoured into 800 ml. of room temperature water, and the flask is rinsedwith 200 ml. of water. The mixture is stirred with the vessel in anice-bath for 15 min., Super Cel is added, the mixture is filtered bysuction, and the cake is washed with 200 ml. water. The layers areseparated, and the aqueous phase is placed in a 2 liter round bottomflask containing 200 ml. ethyl acetate. The internal temperature islowered to 0°-10° C. and the pH is adjusted to 2 by the addition of 5Nsodium hydroxide. Then 100 ml. of a 37.7 percent β-naphthalene sulfonicacid solution is added in about 10 minutes while keeping the pH at 1.5to 1.7 with 5N NaOH. After stirring 6 hr. at 0°-5° C., and no stirringfor 12 hr., the mixture is filtered, and the cake is washed with about100 ml. of cold pH 2 water. After sucking as dry as possible the cake isstirred in 250 ml. of ethyl acetate for 5 minutes, the mixture isfiltered, and the cake is washed with 2 × 50 ml. ethyl acetate, giving137 g. of the above titled product. A portion of the sample is driedindicating 53.5 percent NVM with a corresponding yield of 66 percent,but bioassay vs. S. Lutea indicates 380 γ/mg. with a corresponding yieldof 75 percent. This material is converted to anhydrous ampicillin in 80percent yield by the standard isopropanol/triethylamine procedure asdescribed in U.S. Pat. No. 3,487,073.

EXAMPLE 4 D(-)-α-aminobenzycephalosporin

In a manner similar to the process for preparation of ampicillin inExample 1, but using 7-amino-cephalosporanic acid (54.6 g., 0.2 mole)instead of 6-aminopenicillanic acid, D(-)-α-aminobenzylcephalosporin isisolated by adjusting the pH of the aqueous phase, obtained afterfiltration, to about 5.75.

EXAMPLE 5 naphthalene sulfonic acid salt of D(-)-α-aminobenzylpenicillin

6-Aminopenicillanic acid (21.7 g., 0.1 mole) is stirred indichloromethane (200 ml.) at 0°-5° C., and 14.0 ml. (0.1 mole) oftriethylamine is added, and the mixture is stirred for 1/2 hr. At 0°-5°C., a solution is dripped in of 2-chloro-1,3,2-dioxophopholane (12.7 g.,0.1 mole) in dichloromethane (100 ml.) over a 1 hr. period and stirringis continued at 0°-5° C. for 1/2 hr. D-(-)-phenylglycyl chloridehydrochloride (21.3 g., 0.1 mole) is added all at once and the mixtureis stirred at 0°-5° C. for 30 min. The ice bath is lowered so that onlythe lower 1-2 cm. of the flask is in the ice water, and the internaltemperature is allowed to slowly go to 10° C. over about 2 hr., and themixture is poured into 450 ml. of room temperature water, and the flaskis rinsed with 60 ml. of water. The mixture is stirred with the vesselin an ice bath for 15 min., Super Cell is added, the mixture is filteredby suction, and the cake is washed with 100 ml. of water. The layers areseparated, and the aqueous phase is placed in a 1 liter round bottomflask containing 100 ml. of ethylacetate. The internal temperature islowered to 0°-10° C. and the pH is raised to 2 by the addition of 5NNaOH. Then 60 g. of a 37 percent β-naphthalene sulfonic acid solution isadded within 5 to 10 min. while keeping the pH at 1.5 to 1.7 with 5NNaOH. After stirring overnight at 0°-5° C., the mixture is filtered, andthe cake is washed with cold pH2 water (30 ml.). After sucking as dry aspossible the cake is stirred in 125 ml. of ethyl acetate for 5 min., themixture is filtered, and the cake washed twice with ethyl acetate,giving 38.2 g. of the β-naphthalene sulfonic acid salt ofD(-)-α-aminobenzylpenicillin. A portion of the sample is driedindicating the presence of 6.36 g. of NVM, with a corresponding 44percent yield of the above titled product.

EXAMPLE 6

Following the procedure of Example 1, a series of phosphorylatedpenicillin compounds are prepared by reacting 2 moles of aphosphorylating agent of formula C with one mole of 6-APA to produce acompound of formula D.

    __________________________________________________________________________    R.sup.5                                                                       |                                                                    R.sup.6 --P--X                                                                R.sup.5, R.sup.6,                                                                            X  R.sup.5,          R.sup.6,                                  __________________________________________________________________________    (a)                                                                              CH.sub.3                                                                            CH.sub.3                                                                            Cl CH.sub.3          CH.sub.3                                  (b)                                                                              φ φ Cl φ             φ                                     (c)                                                                              CH.sub.2 φ                                                                       CH.sub.2 φ                                                                     Br  CH.sub.2 φ    CH.sub.2 φ                           (d)            Cl                                                             (e)                                                                              C.sub.2 H.sub.5                                                                      C.sub.2 H.sub.5                                                                    Cl  C.sub.2 H.sub.5   C.sub.2 H.sub.5                          (f)            Cl                                                             (g)            Cl                                                             __________________________________________________________________________

EXAMPLE 7

Following the procedure of Example 4, a series of phosphorylatedpenicillin compounds are prepared by reacting 2 moles of aphosphorylating agent of formula C with one mole of 7-ACA or 7-ADCA toproduce a compound of formula E.

    ______________________________________                                        R.sup.5                                                                       |                                                                    R.sup.6 --P--X                                                                     R.sup.5,                                                                              R.sup.6,                                                                              X    R.sup.2,                                                                            R.sup.5,                                                                            R.sup.6,                                                                            X                                 ______________________________________                                        (a)  CH.sub.3                                                                              CH.sub.3                                                                              Cl   H     CH.sub.3                                                                            CH.sub.3                                                                            Cl                                (b)                  Br   H                 Br                                (c)  φ   φ   F    H     φ φ F                                                           O                                                                             ∥                                          (d)  CH.sub.2 φ                                                                        CH.sub.2 φ                                                                        Cl   OCCH.sub.3                                                                          CH.sub.2 φ                                                                      CH.sub.2 φ                                                                      Cl                                ______________________________________                                    

EXAMPLE 8

Following the procedure of Example 1, a series of phosphorylatedpenicillin compounds are prepared by reacting 0.5 mole of aphosphorylating agent of formula C with one mole of 6-APA to produce acompound of formula F.

    __________________________________________________________________________           R.sup.5                                                                       |                                                                    R.sup.6 --P--X                                                         R.sup.5,                                                                              R.sup.6,                                                                           X R.sup.5,       R.sup.6,                                        __________________________________________________________________________    (a)                                                                              CH.sub.3                                                                           CH.sub.3                                                                           Cl                                                                              CH.sub.3       CH.sub.3                                        (b)                                                                              φ                                                                              φ                                                                              Cl                                                                              φ          φ                                           (c)                                                                              CH.sub.2 φ                                                                     CH.sub.2 φ                                                                     Br                                                                              CH.sub.2 φ CH.sub.2 φ                                  (d)          Cl                                                               (e)                                                                              C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                    Cl                                                                              C.sub.2 H.sub.5                                                                              C.sub.2 H.sub.5                                 (f)          Cl                                                               __________________________________________________________________________

EXAMPLE 9

Following the procedure of Example 4, a series of phosphorylatedcephalosporin compounds are prepared by reacting 0.5 mole of aphosphorylating agent of formula C with one mole of 7-ACA or 7-ADCA toproduce a compound of formula G.

    __________________________________________________________________________           R.sup.5                                                                       |                                                                    R.sup.6 --P--X                                                         R.sup.5,                                                                             R.sup.6,                                                                          X R.sup.2,  R.sup.5,   R.sup.6,                                    __________________________________________________________________________    (a)                                                                              CH.sub.3                                                                          CH.sub.3                                                                          Cl                                                                              H         CH.sub.3   CH.sub.3                                    (b)        Br                                                                              H                                                                (c)                                                                              φ                                                                             φ                                                                             F H         φ      φ                                                    O                                                                             ∥                                                       (d)                                                                              CH.sub.2 φ                                                                    CH.sub.2 φ                                                                    Cl                                                                              OCCH.sub.3                                                                              CH.sub.2 φ                                                                           CH.sub.2 φ                              __________________________________________________________________________

EXAMPLE 10

Following the procedure of Example 1, the following acylating agents areused in place of D(-)phenyl glycine chloride hydrochloride to obtain thefollowing acylated phosphorylated penicillin derivatives. Those havingan amino group are obtained as the hydrochloride salt.

    __________________________________________________________________________    acylating agent                     R                                         __________________________________________________________________________    hydrochloride salt of 1-aminocyclo-                                           pentane carboxylic acid chloride                                              hydrochloride salt of 1-aminocyclo-2-                                         hexene-1-carboxylic acid chloride                                             hydrochloride salt of 1-amino-1-                                              indane carboxylic acid chloride                                               hydrochloride salt of 1-amino-1,2,3,4-                                        tetrahydronaphthoic acid chloride                                             hydrochloride salt of 1-amino-7-ethoxy-                                       1,2,3,4-tetrahydro-1-naphthoic acid                                           chloride                                                                      hydrochloride salt of 2-amino-2-indane-                                       carboxylic acid chloride                                                      hydrochloride salt of 2-amino-1-                                              phenoxy-2-indane carboxylic acid                                              chloride                                                                      hydrochloride salt of 1-amino-1,2,3,4-                                        tetrahydro-3,6-dimethyl-1-naphthoic acid                                      chloride                                                                      hydrochloride salt of 1-amino-3-cyclo-                                        pentene-1-carboxylic acid                                                     3-(phenyl)-5-methyl-4-isoxazole-                                              carbonyl chloride                                                             3-(2',6'-dichlorophenyl)-5-methyl-                                            4-isoxazole-carbonyl chloride                                                 2,6-dimethoxy-benzoic acid chloride                                           2-ethoxy-1-napnthoyl chloride                                                 α-phenoxy butyric acid chloride                                         __________________________________________________________________________

EXAMPLE 11

Following the procedure of Example 4, the acylating agents identifiedbelow are used to obtain the following acylated phosphorylatedcephalosporins. Those having the amino group are obtained as thehydrochloride salt.

    __________________________________________________________________________    acylating agent          R                  R.sup.2                           __________________________________________________________________________    D(-)phenyl glycine chloride,            H                                     hydrochloride                                                                 2-thienylacetic acid                                                          D(-)phenyl glycine chloride,            O                                     hydrochloride                           ∥                                                                    O--C--CH.sub.3                        phenoxyacetic acid chloride             O                                                                             ∥                                                                    O--C--CH.sub.3                        __________________________________________________________________________

It is to be understood that the only limitation on the acyl radical ofthe synthetic penicillins and cephalosporins is that they be essentiallynon-toxic upon in vitro or in vivo application.

The synthetic penicillins and cephalosporins prepared from theintermediates of the present invention have activity against grampositive and/or gram negative bacteria and may be utilized inpharmacological compositions in association with pharmacologicallyacceptable carrier, e.g. in suitable injectable forms, includingsolutions and suspensions; or orally as tablets, capsules, and the like,utilizing conventional solvents, suspensoids, excipients, and the like.These compounds may be administered orally or parenterally. Naturally,the dosage of these compounds will vary somewhat with the form ofadministration and the particular compound chosen. Further, it will varywith the particular subject under treatment.

What is claimed is:
 1. A compound having the following formula which isuseful as an intermediate for obtaining non-toxic penicillins havingantibacterial activity against gram positive and/or gram negativemicroorganisms: ##SPC9##wherein: R² is a member selected from the classconsisting of hydrogen, alkali metal and a tertiary amine; R⁵ and R⁶ areeach selected from the class consisting of (lower)alkyl, phenyl,naphthyl, phenyl(lower)alkyl and naphthyl(lower)alkyl; and R⁵ and R⁶when joined together with the phosphorus atom form the ring: ##SPC10##wherein: X is selected from the class consisting of oxygen, methyleneand sulfur; m is an interger from 1 to 6; R⁷ is selected from the classconsisting of hydrogen and (lower)alkyl.
 2. A compound according toclaim 1 wherein R² is hydrogen.
 3. A compound according to claim 1wherein R⁵ and R⁶ are joined together to form: ##SPC11##wherein X isoxygen and m is one.
 4. A compound according to claim 3 wherein R⁷ ishydrogen.
 5. A compound of the formula: ##SPC12##wherein R⁷ is selectedfrom the class consisting of hydrogen and lower alkyl.
 6. A compoundaccording to claim 5 wherein R⁷ is hydrogen.